The Effect of Angioembolization Versus Open Exploration for Moderate to Severe Blunt Liver Injuries on Mortality.

INTRODUCTION: Blunt liver injury is common and is associated with a high morbidity and mortality. More severe injuries often require either angioembolization or open operative repair, depending on patient factors and facility capacity. We sought to describe patient outcomes based on intervention type. METHODS: We analyzed the National Trauma Data Bank (2017-2019) using ICD-10 codes to identify adult patients with blunt liver injury and their interventions. AIS (Abbreviated Injury Scale) scores were used to group patients based on liver injury severity (AIS 2-6). Logistic regression modeling was used to estimate the adjusted odds ratio of death based on intervention type, excluding patients with severe injury. RESULTS: Of 2,848,592 trauma patients, 50,250 patients had a blunt liver injury. Among patients with AIS 3/4/5 injury, 1,140 had angioembolization, 1,529 had an open repair, and 188 had both angioembolization and open repair. In comparison with no intervention and adjusted for age, sex, shock index, ISS, and transfusion total (first four hours), angioembolization was associated with a significant decrease in the odds of mortality for patients with an AIS 4 (OR 0.68, 95% CI 0.47, 0.99) and AIS 5 injury (OR 0.39, 95% CI 0.24, 0.64). In patients with an AIS 5 injury, open repair had an increased odds of mortality at OR 1.99 (95% CI 1.47, 2.69). CONCLUSION: In an analysis of a national trauma database, patients with a moderate to severe injury (AIS 4 or 5), angioembolization was associated with a significant reduction in the adjusted odds of mortality compared to open repair and should be considered when clinically appropriate.

Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression.

RATIONALE: Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH. OBJECTIVES: Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates. METHODS: We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH. MEASUREMENTS AND MAIN RESULTS: Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-ß pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo. CONCLUSIONS: We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-ß signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis.

Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo.

Adenosine possesses potent anti-inflammatory properties which are partly mediated by G(i) -coupled adenosine A3 receptors (A3Rs). A3R agonists have shown clinical benefit in a number of inflammatory conditions although some studies in A3R-deficient mice suggest a pro-inflammatory role. We hypothesised that, in addition to cell signalling effects, A3R compounds might inhibit neutrophil chemotaxis by disrupting the purinergic feedback loop controlling leukocyte migration. Human neutrophil activation triggered rapid upregulation of surface A3R expression which was disrupted by pre-treatment with either agonist (Cl-IB-MECA) or antagonist (MRS1220). Both compounds reduced migration velocity and neutrophil transmigration capacity without impacting the response to chemokines per se. Similar effects were observed in murine neutrophils, while cells from A3R-deficient mice displayed a constitutively impaired migratory phenotype indicating compound-induced desensitisation and genetic ablation had the same functional outcome. In a dextran sodium sulphate-induced colitis model, A3R-deficient mice exhibited reduced colon pathology and decreased tissue myeloperoxidase levels at day 8 - consistent with reduced neutrophil recruitment. However, A3R-deficient mice were unable to resolve the dextran sodium sulphate-induced inflammation and had elevated numbers of tissue-associated bacteria by day 21. Our data indicate that A3Rs play a role in neutrophil migration and disrupting this function has the potential to adversely affect innate immune responses.

Attenuation of leukocyte recruitment via CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II.

Previous studies from our group have demonstrated that bone morphogenetic protein receptor-II (BMPR-II), expressed on pulmonary artery endothelial cells, imparts profound anti-inflammatory effects by regulating the release of proinflammatory cytokines and promoting barrier function by suppressing the transmigration of leukocytes into the pulmonary vessel wall. Here we demonstrate that, in mice with endothelial-specific loss of BMPR-II expression (L1Cre(+);Bmpr2(f/f)), reduction in barrier function and the resultant pulmonary hypertension observed in vivo are the result of increased leukocyte recruitment through increased CXCR1/2 signaling. Loss of endothelial expressed BMPR-II leads to elevated plasma levels of a wide range of soluble mediators important in regulating leukocyte migration and extravasation, including the CXCR1/2 ligand, KC. Treatment of L1Cre(+);Bmpr2(f/f) mice with the CXCR1/2 antagonist SCH527123 inhibits leukocyte transmigration into lung and subsequently reverses the pulmonary hypertension. Our data have uncovered a previously unrecognized regulatory function of BMPR-II, which acts to regulate the expression of CXCR2 on endothelial cells, suggesting that increased CXCR2 signaling may also be a feature of the human pathology and that CXCR1/2 pathway antagonists may represent a novel therapeutic approach for treating pulmonary hypertension because of defects in BMPR-II expression.

Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.

Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor α or transforming growth factor ß1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression.

Academic detailing to improve appropriate opioid prescribing: a mixed-methods process evaluation.

BACKGROUND: Academic detailing, an educational outreach service for family physicians, was funded by the Ontario government to address gaps in opioid prescribing and pain management. We sought to evaluate the impact of academic detailing on opioid prescribing, and to understand how and why academic detailing may have influenced opioid prescribing. METHODS: In this mixed-methods study, we collected quantitative and qualitative data concurrently from 2017 to 2019 in Ontario, Canada. We analyzed prescribing outcomes descriptively for a sample of participating physicians and compared them with a matched control group. We invited physicians to participate in qualitative interviews to discuss their experiences in academic detailing. Development and analysis of qualitative interviews was informed by the Theoretical Domains Framework. We triangulated qualitative and quantitative findings to understand the mechanisms that drove changes in opioid prescribing. RESULTS: Physicians receiving academic detailing (n = 238) achieved a greater reduction in opioid prescribing than matched controls (n = 238). Seventeen physicians completed interviews and reported that academic detailing addressed barriers to pain care, including lack of confidence, difficult interactions with patients and prescribing and tapering decisions. Academic detailing reinforced knowledge about opioid prescribing and pain management. Discussion of complex patients and talking points to use during challenging conversations were described as key drivers of practice change. INTERPRETATION: The findings of this real-world, mixed-methods evaluation explain how an academic detailing service addressed key barriers and enablers to limit high-risk opioid prescribing in primary care. This nuanced understanding will be used to inform, spread and scale academic detailing.

Effects of an academic detailing service on benzodiazepine prescribing patterns in primary care.

BACKGROUND: Benzodiazepines are commonly used to treat anxiety and/or insomnia but are associated with substantial safety risks. Changes to prescribing patterns in primary care may be facilitated through tailored quality improvement strategies. Academic detailing (AD) may be an effective method of promoting safe benzodiazepine prescribing. The objective of this study was to evaluate the effectiveness of AD on benzodiazepine prescribing among family physicians. METHODS AND FINDINGS: We used an interrupted time series matched cohort design using population-based administrative claims databases. Participants were family physicians practicing in Ontario, Canada. The intervention was a voluntary AD service which involves brief service-oriented educational outreach visits by a trained pharmacist. The focus was on key messages for safer benzodiazepine prescribing in primary care with an emphasis on judicious prescribing to older adults aged 65 and older. Physicians in the intervention group were those who received at least one AD visit on benzodiazepine use between June 2019 and February 2020. Physicians in the control group were included if they did not receive an AD visit during the study period. Intervention physicians were matched to control physicians 1:4, on a variety of characteristics. Physicians were excluded if they had inactive billing or billing of less than 100 unique patient visits in the calendar year prior to the index date. The primary outcome was mean total benzodiazepine prescriptions at the level of the physician. Secondary outcomes were rate (per 100) of patients with long-term prescriptions, high-risk prescriptions, newly started prescriptions, and benzodiazepine-related patient harms. Data were analyzed using a repeated measures pre-post comparison with an intention-to-treat. Analyses were then stratified to focus on effects within higher-prescribing physicians. There were 1337 physicians were included in the study; 237 who received AD and 1064 who did not. There was no significant change in benzodiazepine prescribing when considering all physicians in the intervention and matched control groups. Although not significant, a greater reduction in total benzodiazepine prescriptions was observed amongst the highest-volume prescribing physicians who received the intervention (% change in slope = -0.53, 95%CI = -2.34 to 1.30, p > .05). The main limitation of our study was the voluntary nature of the AD intervention, which may have introduced a self-selection bias of physicians most open to changing their prescribing. CONCLUSION: This study suggests that future AD interventions should focus on physicians with the greatest room for improvement to their prescribing.

Delay of migrating leukocytes by the basement membrane deposited by endothelial cells in long-term culture.

We investigated the migration of human leukocytes through endothelial cells (EC), and particularly their underlying basement membrane (BM). EC were cultured for 20days on 3µm-pore filters or collagen gels to form a distinct BM, and then treated with tumour necrosis factor-α, interleukin-1ß or interferon-γ. Neutrophil migration through the cytokine-treated EC and BM was delayed for 20-day compared to 4-day cultures. The BM alone obstructed chemotaxis of neutrophils, and if fresh EC were briefly cultured on stripped BM, there was again a hold-up in migration. In studies with lymphocytes and monocytes, we could detect little hold-up of migration for 20-day versus 4-day cultures, in either the filter- or gel-based models. Direct microscopic observations showed that BM also held-up neutrophil migration under conditions of flow. Treatment of upper and/or lower compartments of filters with antibodies against integrins, showed that neutrophil migration through the endothelial monolayer was dependent on ß(2)-integrins, but not ß1- or ß(3)-integrins. Migration from the subendothelial compartment was supported by ß1- and ß(2)-integrins for all cultures, but blockade of ß(3)-integrin only inhibited migration effectively for 20-day cultures. Flow cytometry indicated that there was no net increase in expression of ß1- or ß3-integrins during neutrophil migration, and that their specific subendothelial function was likely dependent on turnover of integrins during migration. These studies show that BM is a distinct barrier to migration of human neutrophils, and that ß(3)-integrins are particularly important in crossing this barrier. The lesser effect of BM on lymphocytes and monocytes supports the concept that crossing the BM is a separate, leukocyte-specific, regulated step in migration.

Land use and soil characteristics affect soil organisms differently from above-ground assemblages.

BACKGROUND: Land-use is a major driver of changes in biodiversity worldwide, but studies have overwhelmingly focused on above-ground taxa: the effects on soil biodiversity are less well known, despite the importance of soil organisms in ecosystem functioning. We modelled data from a global biodiversity database to compare how the abundance of soil-dwelling and above-ground organisms responded to land use and soil properties. RESULTS: We found that land use affects overall abundance differently in soil and above-ground assemblages. The abundance of soil organisms was markedly lower in cropland and plantation habitats than in primary vegetation and pasture. Soil properties influenced the abundance of soil biota in ways that differed among land uses, suggesting they shape both abundance and its response to land use. CONCLUSIONS: Our results caution against assuming models or indicators derived from above-ground data can apply to soil assemblages and highlight the potential value of incorporating soil properties into biodiversity models.

Earthworm distributions are not driven by measurable soil properties. Do they really indicate soil quality?

Abundance and distribution of earthworms in agricultural fields is frequently proposed as a measure of soil quality assuming that observed patterns of abundance are in response to improved or degraded environmental conditions. However, it is not clear that earthworm abundances can be directly related to their edaphic environment, as noted in Darwin's final publication, perhaps limiting or restricting their value as indicators of ecological quality in any given field. We present results from a spatially explicit intensive survey of pastures within United Kingdom farms, looking for the main drivers of earthworm density at a range of scales. When describing spatial variability of both total and ecotype-specific earthworm abundance within any given field, the best predictor was earthworm abundance itself within 20-30 m of the sampling point; there were no consistent environmental correlates with earthworm numbers, suggesting that biological factors (e.g. colonisation rate, competition, predation, parasitism) drive or at least significantly modify earthworm distributions at this spatial level. However, at the national scale, earthworm abundance is well predicted by soil nitrate levels, density, temperature and moisture content, albeit not in a simple linear fashion. This suggests that although land can be managed at the farm scale to promote earthworm abundance and the resulting soil processes that deliver ecosystem services, within a field, earthworm distributions will remain patchy. The use of earthworms as soil quality indicators must therefore be carried out with care, ensuring that sufficient samples are taken within field to take account of variability in earthworm populations that is unrelated to soil chemical and physical properties.

Ultrasound mimics the effect of mechanical loading on bone formation in vivo on rat ulnae.

While the effect of ultrasound as an extreme example of low-magnitude high-frequency stimulation has been explored in the response of bone to injury, little is known about its effect on normal bone. This experiment was designed to test the hypothesis that ultrasound exerts a similar influence on bone as mechanical stimulation at a physiological level. Three groups of female Wistar rats were anaesthetised (6 per group). In one group, the left ulna was loaded cyclically in vivo 40 times, repeated on a further 5 occasions on alternate days. In a second group, transcutaneous low-intensity pulsed ultrasound stimulation was applied to the left ulnae for the same duration as the period of loading. In a third group, loading and ultrasound stimulation were applied concurrently. The right ulna served as non-loaded control in each animal. At the end of the experiment after 14 days, both ulnae were removed. Induced bone formation was assessed by measuring the proportion of medial periosteal bone surface with double label (dLS/BS, %) and by calculation of mineral apposition rate (MAR) from the inter-label distance. All three treatments induced a significant periosteal response, increasing dLS/BS values from <10% in control limbs to >80% in treated limbs. Increases in MAR of experimental ulnae versus contralateral control ulnae were 2.9 (+/-0.9), 8.6 (+/-2.4) and 8.7 microm (+/-3.2) for the ultrasound only, ultrasound and load, and load only groups, respectively. The effects of loading plus ultrasound were not significantly different from ultrasound alone. These data suggest that ultrasound is able to induce changes in bone that share at least some features with mechanical loading.

Service Provider Difficulties in Operationalizing Coercive Control.

We examined perspectives of social workers, police officers, and specialist domestic abuse practitioners about their perceived ability and organizational readiness to respond effectively to incidents of coercive and controlling behavior. Interviews revealed intervention and risk assessment strategies structured around an outdated, maladaptive concept of domestic abuse as an unambiguous and violent event and frontline services that lacked appreciation of the power dynamics inherent in controlling relationships. The analysis demonstrates how lack of definitional clarity around nonphysical domestic abuse can increase the use of discretion by frontline services and, by extension, increase the discounting of coercive control by pressured frontline officers.

The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project.

The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.

Has land use pushed terrestrial biodiversity beyond the planetary boundary? A global assessment.

Land use and related pressures have reduced local terrestrial biodiversity, but it is unclear how the magnitude of change relates to the recently proposed planetary boundary ("safe limit"). We estimate that land use and related pressures have already reduced local biodiversity intactness--the average proportion of natural biodiversity remaining in local ecosystems--beyond its recently proposed planetary boundary across 58.1% of the world's land surface, where 71.4% of the human population live. Biodiversity intactness within most biomes (especially grassland biomes), most biodiversity hotspots, and even some wilderness areas is inferred to be beyond the boundary. Such widespread transgression of safe limits suggests that biodiversity loss, if unchecked, will undermine efforts toward long-term sustainable development.

PLCE1 mRNA and protein expression and survival of patients with esophageal squamous cell carcinoma and gastric adenocarcinoma.

BACKGROUND: Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival. METHODS: PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124). RESULTS: Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; Ptrend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; Ptrend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; Ptrend = 0.04). CONCLUSIONS: Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis. IMPACT: A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation.

Validation of esophageal squamous cell carcinoma candidate genes from high-throughput transcriptomic studies.

In a recent study, a unique gene expression signature was observed when comparing esophageal squamous cell carcinoma (ESCC) epithelial cells to normal esophageal epithelial cells using laser capture microdissection (LCM) and cDNA microarray technology. To validate the expression of several intriguing genes from that study (KRT17, cornulin, CD44, and EpCAM), we employed two new technologies, expression microdissection (xMD) for high-throughput microdissection facilitating protein analysis and RNAscope for the evaluation of low abundant transcripts in situ. For protein measurements, xMD technology was utilized to specifically procure sufficient tumor and normal epithelium from frozen human tissue for immunoblot analysis of KRT17 (CK17) and cornulin. A novel in situ hybridization method (RNAscope) was used to determine the transcript level of two relatively low expressed genes, CD44 and EpCAM in both individual formalin-fixed paraffin-embedded (FFPE) tissue sections and in an ESCC tissue microarray (TMA). The results successfully confirmed the initial expression pattern observed for all four genes, potentially implicating them in the pathogenesis of ESCC. Additionally, the study provides important methodological information on the overall process of candidate gene validation.

LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans.

The highly conserved let-7 microRNA (miRNA) regulates developmental pathways across animal phyla. Mis-expression of let-7 causes lethality in C. elegans and has been associated with several human diseases. We show that timing of let-7 expression in developing worms is under complex transcriptional and post-transcriptional control. Expression of let-7 primary transcripts oscillates during each larval stage, but precursor and mature let-7 miRNAs do not accumulate until later in development after LIN-28 protein has diminished. We demonstrate that LIN-28 binds endogenous primary let-7 transcripts co-transcriptionally. We further show that LIN-28 binds endogenous primary let-7 transcripts in the nuclear compartment of human ES cells, suggesting that this LIN-28 activity is conserved across species. We conclude that co-transcriptional interaction of LIN-28 with let-7 primary transcripts blocks Drosha processing and, thus, precocious expression of mature let-7 during early development.